Targeting the Vulnerability of Glutathione Metabolism in ARID1A-Deficient Cancers

Hideaki Ogiwara; Kazuaki Takahashi; Mariko Sasaki; Takafumi Kuroda; Hiroshi Yoshida; Reiko Watanabe; Ami Maruyama; Hideki Makinoshima; Fumiko Chiwaki; Hiroki Sasaki; Tomoyasu Kato; Aikou Okamoto; Takashi Kohno

doi:10.1016/j.ccell.2018.12.009

Targeting the Vulnerability of Glutathione Metabolism in ARID1A-Deficient Cancers

Cancer Cell. 2019 Feb 11;35(2):177-190.e8. doi: 10.1016/j.ccell.2018.12.009. Epub 2019 Jan 24.

Authors

Affiliations

¹ Division of Genome Biology, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. Electronic address: hogiwara@ncc.go.jp.
² Division of Genome Biology, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Department of Obstetrics and Gynecology, The Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan.
³ Division of Genome Biology, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Molecular Oncology, The Jikei University Graduate School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan.
⁴ Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
⁵ Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, Yamagata 997-0052, Japan; Shonai Regional Industry Promotion Center, Tsuruoka, Yamagata 997-0015, Japan.
⁶ Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, Yamagata 997-0052, Japan.
⁷ Department of Translational Oncology, Fundamental Innovative Oncology Core Center, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
⁸ Department of Gynecology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
⁹ Department of Obstetrics and Gynecology, The Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan.
¹⁰ Division of Genome Biology, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Molecular Oncology, The Jikei University Graduate School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan. Electronic address: tkkohno@ncc.go.jp.

PMID: 30686770
DOI: 10.1016/j.ccell.2018.12.009

Abstract

ARID1A encodes an SWI/SNF chromatin-remodeling factor and is frequently mutated in various cancers. This study demonstrates that ARID1A-deficient cancer cells are specifically vulnerable to inhibition of the antioxidant glutathione (GSH) and the glutamate-cysteine ligase synthetase catalytic subunit (GCLC), a rate-limiting enzyme for GSH synthesis. Inhibition of GCLC markedly decreased GSH in ARID1A-deficient cancer cells, leading to apoptotic cell death triggered by excessive amounts of reactive oxygen species. The vulnerability of ARID1A-deficient cancer cells results from low basal levels of GSH due to impaired expression of SLC7A11. The SLC7A11-encoded cystine transporter supplies cells with cysteine, a key source of GSH, and its expression is enhanced by ARID1A-mediated chromatin remodeling. Thus, ARID1A-deficient cancers are susceptible to synthetic lethal targeting of GCLC.

Keywords: APR-246; ARID1A; GCLC; SWI/SNF chromatin-remodeling complex; glutathione; ovarian cancer; ovarian clear cell carcinoma; reactive oxygen species; synthetic lethality; vulnerability.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Transport System y+ / genetics
Amino Acid Transport System y+ / metabolism
Animals
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects*
DNA-Binding Proteins
Enzyme Inhibitors / pharmacology*
Female
Glutamate-Cysteine Ligase / antagonists & inhibitors*
Glutamate-Cysteine Ligase / metabolism
Glutathione / metabolism*
HCT116 Cells
Humans
Mice, Inbred BALB C
Mice, Nude
Molecular Targeted Therapy
Nuclear Proteins / deficiency*
Nuclear Proteins / genetics
Ovarian Neoplasms / drug therapy*
Ovarian Neoplasms / genetics
Ovarian Neoplasms / metabolism
Ovarian Neoplasms / pathology
Oxidative Stress / drug effects*
Quinuclidines / pharmacology*
Transcription Factors / deficiency*
Transcription Factors / genetics
Tumor Cells, Cultured
Xenograft Model Antitumor Assays

Substances

ARID1A protein, human
Amino Acid Transport System y+
Antineoplastic Agents
DNA-Binding Proteins
Enzyme Inhibitors
Nuclear Proteins
Quinuclidines
SLC7A11 protein, human
Transcription Factors
GCLC protein, human
Glutamate-Cysteine Ligase
Glutathione
eprenetapopt